EP1601359B1 - Formulations pharmaceutiques liquides de palonosetron - Google Patents

Formulations pharmaceutiques liquides de palonosetron Download PDF

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Publication number
EP1601359B1
EP1601359B1 EP04706657A EP04706657A EP1601359B1 EP 1601359 B1 EP1601359 B1 EP 1601359B1 EP 04706657 A EP04706657 A EP 04706657A EP 04706657 A EP04706657 A EP 04706657A EP 1601359 B1 EP1601359 B1 EP 1601359B1
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Prior art keywords
palonosetron
solution
acid
pharmaceutically acceptable
mannitol
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EP04706657A
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German (de)
English (en)
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EP1601359A1 (fr
Inventor
Giorgio Calderari
Daniele Bonadeo
Roberta Cannella
Enrico Braglia
Riccardo Braglia
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Helsinn Healthcare SA
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Helsinn Healthcare SA
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Priority to SI200430976T priority Critical patent/SI1601359T1/sl
Priority to EP08015410A priority patent/EP2008659A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4747—Quinolines; Isoquinolines spiro-condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B3/00—Packaging plastic material, semiliquids, liquids or mixed solids and liquids, in individual containers or receptacles, e.g. bags, sacks, boxes, cartons, cans, or jars
    • B65B3/04—Methods of, or means for, filling the material into the containers or receptacles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B55/00—Preserving, protecting or purifying packages or package contents in association with packaging
    • B65B55/02—Sterilising, e.g. of complete packages

Definitions

  • the present invention relates to shelf-life stable liquid formulations of palonosetron that are especially useful in the preparation of injectable and oral medicaments in the form of pharmaceutical solutions comprising :
  • 5-HT 3 (5-hydroxytryptamine) receptor antagonists
  • Drugs within this class include ondansetron, granisetron, alosetron, tropisetron, and dolasetron.
  • 5-HT 3 antagonists are often administered intravenously shortly before chemotherapy or radiotherapy is initiated, and can be administered more than once during a cycle of chemotherapy or radiotherapy.
  • they are often supplied as tablets or oral elixirs to either supplement an intravenous administration, or to ease home usage of the drug if the patient is self-administering the chemotherapeutic regimen.
  • chemotherapeutic agents can induce emesis over extended periods of several days even when they are administered only once, it would be desirable to administer an emesis-inhibiting drug such as a 5-HT 3 antagonist every day until the risk of emesis has substantially subsided.
  • an emesis-inhibiting drug such as a 5-HT 3 antagonist every day until the risk of emesis has substantially subsided.
  • the present class of 5-HT 3 antagonists has not proven especially helpful meeting this need, however, because the 5-HT 3 receptor antagonists currently marketed have proven to be less effective in controlling delayed nausea and vomiting than they are at controlling acute emesis.
  • Sabra, K Choice of a 5HT3 Receptor Antagonist for the Hospital Formulary. EHP, Oct. 1996;2 (suppl 1):S19-24 .
  • U.S. Pat. No. 5,202,333 discloses an intravenous formulation of palonosetron in example 13 that contains the following ingredients: Ingredient Mg Palonosetron HCI 10-100 mg. Dextrose Monohydrate q.s. to make Isotonic Citric Acid Monohydrate 1.05 mg. Sodium Hydroxide 0.18 mg. WFJ To 1.0 ml.
  • the formulation has a pH of 3.7 and a shelf stability of less than the 1-2 year time period required by health authorities in various countries.
  • Ondansetron its uses, and medicaments made with ondansetron are disclosed in U.S. Patent Numbers 4,695,578 , 4,753,789 , 4,929,632 , 5,240,954 , 5,344,658 , 5,578,628 , 5,578,632 , 5,922,749 , 5,622,720 , 5,955,488 , and 6,063,802 .
  • Zofran® Commercially it is distributed by GlaxoSmithKline as Zofran® and is indicated for prevention of postoperative nausea and vomiting (PONV), cancer chemotherapy-induced nausea and vomiting (CINV), and radiotherapy-induced nausea and vomiting (RINV) and it is available as an injection, tablets and solution, and as Zofran ODT® (ondansetron) Orally Disintegrating Tablets.
  • PONV postoperative nausea and vomiting
  • CINV cancer chemotherapy-induced nausea and vomiting
  • RINV radiotherapy-induced nausea and vomiting
  • Granisetron its uses, and medicaments made with granisetron are disclosed in U.S. Patent Numbers 4,886,808 , 4,937,247 , 5,034,398 and 6,294,548 .
  • Kytril® indicated for the prevention of nausea and vomiting associated with chemotherapy or radiation therapy, and is offered in tablet form, oral solution, and as an injection.
  • Alosetron, its uses, and medicaments made with alosetron are disclosed in U.S. Patent Numbers 5,360,800 and 6,284,770 . Commercially it is distributed by GlaxoSmithKline as Lotronex®.
  • Tropisetron is commercially available as Navoban® (Novartis) CAS - 89565-68-4 (tropisetron); CAS - 105826-92-4 (tropisetron hydrochloride) and it is indicated for treatment of PONV and CINV.
  • Dolasetron its uses, and medicaments made with ondansetron are disclosed in U.S. Patent Numbers 5,011,846 , and 4,906,755 .
  • Commercially it is distributed by Aventis Pharmaceuticals Inc. as Anzemet®, indicated for prevention of both PONV and CINV, and it is offered in the form of a tablet or an intravenous solution.
  • the inventors have made a series of discoveries that support a surprisingly effective and versatile formulation for the treatment and prevention of emesis using palonosetron. These formulations are shelf stable for periods greater than 24 months at room temperature, and thus can be stored without refrigeration, and manufactured using non-aseptic, terminal sterilization processes.
  • the inventors have discovered that formulations which include the active ingredient palonosetron require in some instances only 1/10 th the amount of other previously known compounds for treating emesis, which surprisingly allows the use of concentrations of palonosetron far below those that would ordinarily be expected.
  • the invention provides a pharmaceutically stable solution for preventing or reducing emesis comprising a) from about 0.03 mg/mL to about 0.2 mg/mL palonosetron hydrochloride; and b) a pharmaceutically acceptable carrier at a pH of from 4.0 to 6.0 comprising a chelating agent.
  • the invention provides a pharmaceutically stable solution for preventing or reducing emesis as defined above, also comprising from about 10 to about 100 millimoles citrate buffer; and from about 0.005 to about 1.0 mg/ml EDTA.
  • the invention provides a pharmaceutically stable solution for preventing or reducing emesis as defined above and also comprising
  • Vial means a small glass container sealed with the most suitable stopper and seal, other suitable primary containers may be used, for instance, but not limited to, prefilled syringes. Vial also means a sealed container of medication that is used one time only, and includes breakable and non-breakable glass vials, breakable plastic vials, miniature screw-top jars, and any other type of container of a size capable of holding only one unit dose ofpalonosetron (typically about 5 mls.).
  • Palonosetron means (3aS)-2,3,3a,4,5,6-Hexahydro-2-[(S)-1-Azabicyclo[2.2.2]oct-3-yl]2,3,3a,4,5,6-hexahydro-1-oxo-1 H benz[ de ]isoquinoline, and is preferably present as the monohydrochloride.
  • Palonosetron monohydrochloride can be represented by the following chemical structure:
  • Concentrations When concentrations of palonosetron are given herein, the concentration is measured in terms of the weight of the free base. Concentrations of all other ingredients are given based on the weight of ingredient added to the solution.
  • “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salts” means salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2,-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic
  • pharmaceutically acceptable salts may be formed when an acidic proton present is capable of reacting with inorganic or organic bases.
  • Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide.
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
  • the invention provides a pharmaceutically stable solution for preventing or reducing emesis comprising a) from about 0.03 mg/mL to about 0.2 mg/mL palonosetron hydrochloride and b) a pharmaceutically acceptable carrier at a pH of from 4.0 to 6.0 comprising a chelating agent.
  • the invention provides a method of formulating a pharmaceutically stable solution of palonosetron HCl comprising admixing from about 0.03 g/mL to about 0.2 mg/mL palonosetron HCl with a pharmaceutically acceptable carrier at a pH of from 4.0 to 6.0 comprising a chelating agent.
  • the formulation includes palonosetron HCl in a concentration most optimally about 0.05 mg/ml.
  • a particular advantage associated with the lower dosages of intravenous palonosetron is the ability to administer the drug in a single intravenous bolus over a short, discrete time period. This time period generally extends from about 10 to about 60 seconds, or about 10 to about 40 seconds, and most preferably is about 10 to 30 seconds.
  • the palonosetron is supplied in vials that comprise 5 ml. of solution, which equates to about 0.25 mg of palonosetron at a concentration of about 0.05 mg/ml.
  • the inventors have further discovered that by adjusting the formulation's pH and/or excipient concentrations it is possible to increase the stability of palonosetron formulations.
  • the pH is from about 4.5 to about 5.5, and most optimally about 5.0.
  • suitable solutions to adjust the pH of a formulation Two exemplary solutions are sodium hydroxide and hydrochloric acid solution, either of which could be used to adjust the pH of the formulation.
  • the invention provides a pharmaceutically stable solution for preventing or reducing emesis comprising from about 0.03 to about 0.2 mg/ml palonosetron HCl and (i) from about 10 to about 100 millimoles citrate buffer, and/or (ii) from about 0.005 to about 1.0 mg/ml EDTA in a pharmaceutically acceptable carrier at a pH of from 4.0 to 6.0.
  • the invention provides a method of formulating a pharmaceutically stable solution of palonosetron comprising admixing from about 0.03 to about 0.2 mg/ml palonosetron HCl and (i) from about 10 to about 100 millimoles citrate buffer, and/or (ii) from about 0.005 to about 1.0 mg/ml EDTA in a pharmaceutically acceptable carrier at a pH of from 4.0 to 6.0.
  • the citrate buffer can be in the form of citric acid and/or a salt of citric acid such as trisodium citrate.
  • the ranges of one or more of the foregoing ingredients can be modified as follows:
  • the invention provides a pharmaceutically stable solution for preventing or reducing emesis comprising a) palonosetron HCl at a concentration from 0.03 mg/ml to 0.2 mg/ml b) a pharmaceutically acceptable carrier at a pH of from 4.0 to 6.0, wherein the pharmaceutically acceptable carrier comprises a chelating agent and mannitol.
  • the invention provides a method of formulating a pharmaceutically stable solution of palonosetron comprising admixing a) palonosetron HCl at a concentration from 0.03 mg/ml to 0.2 mg/ml and b) a pharmaceutically acceptable carrier at a pH of from 4.0 to 6.0, wherein the pharmaceutically acceptable carrier comprises a chelating agent and mannitol.
  • the chelating agent is preferably EDTA, and, in various embodiments the chelating agent is present in a concentration of from about 0.005 to about 1.0 mg/mL or from about 0.05 mg/mL to about 1.0 mg/mL or from about 0.3 to about 0.7 mg/ml, or most optimally about 0.5 mg/ml.
  • the mannitol is present in a concentration of from about 10.0 mg/ml to about 80.0 mg/ml, from about 20.0 mg/mL to about 60.0 mg/ml, or from about 40.0 to about 45.0 mg/ml.
  • Injectable formulations are typically formulated as aqueous solutions in which water is the primary excipient. Oral formulations will differ from injectable formulations generally by the additional presence of flavoring agents, coloring agents, or viscosity agents.
  • Natural or synthetic sweeteners include, among others, mannitol, sorbitol, saccharose, saccharine, aspartame, acelsulphame K, or cyclamate. These agents are generally present in concentrations in excess of 100 mg/ml or 250 mg/ml when used as sweetening agents, in contrast to the 41.5 mg/ml concentration of mannitol described in some of the embodiments of the invention, in which mannitol is acting simply as a tonicifying agent.
  • the formulations of the present invention are particularly suited for use in injectable and oral liquid formulations, but it will be understood that the solutions may have alternative uses. For example, they may be used as intermediates in the preparation of other pharmaceutical dosage forms. Similarly, they may have other routes of administration including intranasal or inhalation. Injectable formulations may take any route including intramuscular, intravenous or subcutaneous.
  • the invention provides a method of storing one or more containers in which are contained a solution of palonosetron or a pharmaceutically acceptable salt thereof comprising: a) providing a room comprising said one or more containers; b) adjusting or maintaining the temperature of the room at greater than about ten, 15, or 20 degrees celcius; and c) storing said containers in said room for one month, 3 months, 6 months, one year, 18 months, 24 months or more (but preferably not exceeding 36 months), wherein (i) the palonosetron HCl is present in a concentration of from about 0.03 mg/mL to about 0.2 mg/mL, (ii) the pH of the solution is from about 4.0 to about 6.0, (iii) the solution comprises from about 10 to about 100 millimoles citrate buffer and from
  • the invention provides a method of filling a container in which is contained a solution of palonosetron or a pharmaceutically acceptable salt thereof comprising: a) providing one or more sterile open containers (preferably 5 ml.
  • vials b) filling said containers with a solution of palonosetron in a non-aseptic environment; c) sealing said filled containers; and d) sterilizing said sealed, filled containers, wherein (i) the palonosetron HCl is present in a concentration of from about 0.03 mg/mL to about 0.2 mg/mL, (ii) the pH of the solution is from about 4.0 to about 6.0, (iii) the solution comprises from about 10 to about 100 millimoles citrate buffer and from about 0.005 to about 1.0 mg/ml EDTA chelating agent.
  • the palonosetron HCl is present in a concentration of from about 0.03 mg/mL to about 0.2 mg/mL
  • the pH of the solution is from about 4.0 to about 6.0
  • the solution comprises from about 10 to about 100 millimoles citrate buffer and from about 0.005 to about 1.0 mg/ml EDTA chelating agent.
  • a formulation optimization study was performed using an experimental design software. Twenty-four lots of drug product were analyzed to investigate the appropriate concentration ranges for palonosetron hydrochloride (0.05 mg/mL to 5.0 mg/mL), citrate buffer (0 to 80 mM) and EDTA (0 to 0.10%). The level of EDTA and citrate buffer were selected based on the optimal formulation, which was shown to be formulated with EDTA 0.05% and 20 mM citrate buffer at pH 5.0. The results of this study indicated that palonosetron concentration was also a critical factor in chemical stability, with greatest stability seen at the lowest palonosetron concentrations.
  • Formulations of palonosetron hydrochloride in citrate buffer were prepared including either a) sodium chloride or b) mannitol.
  • the palonosetron hydrochloride formulation including mannitol showed superior stability.
  • the optimum level of mannitol required for an isotonic solution was found to be 4.15%.
  • the physical and chemical stability of palonosetron HCl was studies in concentrations of 5 ⁇ g/mL and 30 ⁇ g/mL in 5% dextrose injection, 0.9% sodium chloride injection, 5% dextrose in 0.45% sodium chloride injection, and dextrose 5% in lactated Ringer's injection.
  • the admixtures were evaluated over 14 days at 4 °C in the dark and for 48 hours at 23 °C under fluorescent light.
  • Test samples ofpalonosetron HCl were prepared in polyvinyl chloride (PVC) bags of the infusion solutions at concentrations of 5 and 30 ⁇ g/mL. Evaluations for physical and chemical stability were performed on samples taken initially and after 1, 3, 5, 7, and 14 days of storage at 4 °C and after 1, 4, 24, and 48 hours at 23 °C. Physical stability was assessed using visual observation in normal room light and using a high-intensity monodirectional light beam. In addition, turbidity and particle content were measured electronically. Chemical stability of the drug was evaluated by using a stability-indicating high performance liquid chromatographic (HPLC) analytical technique.
  • HPLC high performance liquid chromatographic
  • test samples of palonosetron HCl 5 ⁇ g/mL with dexamethasone (as sodium phosphate) 0.2 mg/mL and also 0.4 mg/mL were prepared in polyvinyl chloride (PVC) minibags of each infusion solution. Additionally, palonosetron HCl 25 ⁇ g/mL with dexamethasone (as sodium phosphate) 0.33 mg/mL in each infusion solution were prepared as 10 mL of test solution in 20-mL polypropylene syringes. Evaluations for physical and chemical stability were performed on samples taken initially and after 1, 3, 7, and 14 days of storage at 4 °C and after 1, 4, 24, and 48 hours at 23 °C.

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Claims (11)

  1. Solution pharmaceutiquement stable destinée à prévenir ou réduire les vomissements, qui comprend :
    a) de 0,03 mg/mL à 0,2 mg/mL de chlorhydrate de palonosétron et
    b) un vecteur pharmaceutiquement acceptable à un pH de 4,0 à 6,0, comprenant un agent chélateur.
  2. Solution selon la revendication 1, dans laquelle la concentration du chlorhydrate de palonosétron est de 0,05 mg/mL.
  3. Solution selon la revendication 1, dans laquelle le pH est de 4,5 à 5,5.
  4. Solution selon la revendication 1, dans laquelle le vecteur pharmaceutiquement acceptable comprend de 0,005 mg/mL à 1,0 mg/mL d'EDTA.
  5. Solution selon la revendication 1, dans laquelle le vecteur pharmaceutiquement acceptable comprend du mannitol.
  6. Solution selon la revendication 1, adaptée pour une administration par voie intraveineuse.
  7. Solution selon la revendication 1, adaptée pour une administration par voie orale.
  8. Solution selon l'une quelconque des revendications précédentes, qui est présente sous la forme d'une unité posologique comprenant 5 mL de solution dans un flacon.
  9. Solution selon la revendication 1, qui comprend du chlorhydrate de palonosétron, du mannitol, un tampon citrate 10 à 100 mmoles, et de l'eau, à un pH de 4,5 à 5,5.
  10. Solution selon la revendication 9, qui comprend 0,05 mg/mL de chlorhydrate de palonosétron, en se basant sur la base libre, 41,5 mg/mL de mannitol, 0,5 mg/mL d'EDTA, 3,7 mg/mL de citrate trisodique, 1,56 mg/mL d'acide citrique, et de l'eau q.s. jusqu'à 1 mL, à un pH de 4,5 à 5,5.
  11. Utilisation (i) d'une solution ayant un pH compris entre 4,0 et 6,0 ; (ii) d'un tampon citrate 10 à 100 mmoles ; (iii) de 0,005 à 1,0 mg/mL d'EDTA ; et (iv) de mannitol, pour conférer une stabilité à une solution injectable de palonosétron ou d'un sel pharmaceutiquement acceptable de celui-ci, le palonosétron ou le sel pharmaceutiquement acceptable de celui-ci étant présent à une concentration de 0,03 mg/mL à 0,2 mg/mL.
EP04706657A 2003-01-30 2004-01-30 Formulations pharmaceutiques liquides de palonosetron Revoked EP1601359B1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
SI200430976T SI1601359T1 (sl) 2003-01-30 2004-01-30 Tekoče farmacevtske formulacije palonosetrona
EP08015410A EP2008659A1 (fr) 2003-01-30 2004-01-30 Formules pharmaceutiques liquides de palonosétron
CY20081101485T CY1108660T1 (el) 2003-01-30 2008-12-22 Υγρες φαρμακευτικες τυποποιησεις παλονοσετρονης

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US44435103P 2003-01-30 2003-01-30
US444351P 2003-01-30
PCT/EP2004/000888 WO2004067005A1 (fr) 2003-01-30 2004-01-30 Formulations pharmaceutiques liquides de palonosetrone

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IS7984A (is) 2005-08-15
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US20110192493A1 (en) 2011-08-11
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US7947725B2 (en) 2011-05-24
EP1601359A1 (fr) 2005-12-07
PE20050066A1 (es) 2005-04-20
SI1601359T1 (sl) 2009-04-30
AP2110A (en) 2010-03-01
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JO2735B1 (en) 2013-09-15
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UA90449C2 (ru) 2010-05-11
NO329500B1 (no) 2010-11-01
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ATE410167T1 (de) 2008-10-15
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US20060167073A1 (en) 2006-07-27
US20130267553A1 (en) 2013-10-10
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